The discovery of a single molecule is rewriting the story of this common autoimmune disorder.
By Research Digest | Updated June 2025
For decades, celiac disease was thought to be a straightforward story of genetics meeting gluten. If you had the right human leukocyte antigen (HLA) genes and ate gluten, your immune system would eventually revolt, damaging your small intestine.
While nearly 40% of the genetic risk for celiac disease comes from HLA genes, this only tells part of the story 1 . The rest of the risk comes from other genetic regions, many located in the vast, mysterious parts of our genome that don't code for proteins—once dismissively called "junk DNA."
Recently, scientists discovered a crucial character in this story: a long noncoding RNA called lnc13. This discovery is revolutionizing our understanding of what triggers celiac disease and opens up exciting new possibilities for treatment.
To understand why lnc13 is so important, we first need to explore the hidden world of noncoding RNAs. Imagine your genome as a library. Only about 2% of the books (genes) contain instructions for building proteins—the workhorses of your cells 1 . The other 98% were once considered filler, but we now know they are filled with crucial regulatory information, much of it for producing noncoding RNAs.
These noncoding RNAs are the managers and coordinators of your genome. Three key types play a role in celiac disease:
Short RNA strands that typically silence genes by blocking protein production 1 .
Unique loop-shaped RNAs that can act like sponges, soaking up miRNAs to prevent them from silencing genes 1 .
RNA molecules longer than 200 nucleotides that regulate gene expression in various ways, often acting as master switches for inflammatory responses 1 .
These molecules help explain why having "celiac genes" doesn't guarantee you'll develop the disease—epigenetic factors can turn their activity up or down.
| Type | Length | Primary Function | Role in Celiac Disease |
|---|---|---|---|
| microRNA (miRNA) | ~18-22 nucleotides | Silences gene expression by degrading target mRNA or blocking translation | Multiple miRNAs show altered expression in celiac patients, contributing to inflammation |
| Long Noncoding RNA (lncRNA) | >200 nucleotides | Regulates gene expression through various mechanisms including chromatin modification | lnc13 represses inflammatory genes; its decrease may trigger celiac inflammation |
| Circular RNA (circRNA) | Hundreds to thousands of nucleotides | Acts as miRNA sponge, regulating gene expression indirectly | Emerging research suggests circRNAs may be involved in disease pathways |
The story of lnc13 begins with a mystery in chromosome 2. Genome-wide association studies had identified a region containing several single-nucleotide polymorphisms (SNPs) associated with celiac disease, but no protein-coding genes appeared to be responsible 2 . This region was close to the IL18RAP gene, which is involved in immune responses, but the celiac-associated SNPs weren't actually within this gene.
Scientists discovered that this region corresponds to a lncRNA, which they named lnc13 2 . Although part of lnc13 overlaps with the IL18RAP gene, they confirmed these are independent transcripts with separate functions and regulation.
lnc13 levels were significantly decreased in the small intestinal tissues of people with active celiac disease compared to healthy controls 2 .
The most striking finding emerged when researchers examined intestinal biopsy samples from celiac patients: lnc13 levels were significantly decreased in the small intestinal tissues of people with active celiac disease compared to healthy controls 2 . Meanwhile, the nearby IL18RAP gene showed increased activity, suggesting that lnc13 normally helps keep inflammatory genes in check.
To understand how lnc13 works, scientists conducted a series of elegant experiments that revealed its role as a molecular brake on inflammation.
Through precise mapping techniques, they first verified that lnc13 and IL18RAP are separate molecules, despite their genomic proximity 2 .
Using RNA in situ hybridization, they determined that lnc13 primarily resides in the nucleus of immune cells in the intestinal lamina propria—the layer of connective tissue beneath the intestinal lining 2 .
They stimulated mouse and human immune cells with lipopolysaccharide (LPS), a molecule that mimics inflammatory infection, and observed that lnc13 levels significantly decreased upon inflammation 2 .
By testing cells lacking key inflammatory signaling proteins, they discovered that lnc13 reduction depends on both MyD88 and NF-κB pathways—two crucial players in immune responses 2 .
The team examined how altering lnc13 levels affected other genes, finding that increasing lnc13 suppressed multiple inflammatory genes, while decreasing lnc13 enhanced their expression 2 .
lnc13 acts as a molecular dimmer switch for inflammation. It binds to hnRNPD protein to repress pro-inflammatory genes.
Gluten triggers immune response, activating NF-κB pathway and increasing Dcp2 enzyme production.
Dcp2 destabilizes lnc13, causing its levels to drop. With the brake released, inflammatory genes become active.
The experiments painted a clear picture of lnc13's function:
In healthy conditions, lnc13 acts as a molecular dimmer switch for inflammation. It binds to a protein called hnRNPD, and together they repress a set of pro-inflammatory genes, including TRAF2, STAT1, and MYD88 2 . These genes are involved in signaling pathways that can trigger the excessive immune response seen in celiac disease.
When inflammation occurs—such as when gluten triggers an immune response in susceptible individuals—the NF-κB pathway activates and increases production of a decapping enzyme called Dcp2. This enzyme destabilizes lnc13, causing its levels to drop 2 . With the brake released, inflammatory genes become active, launching the immune attack that damages intestinal tissue.
| Gene | Function in Immune Response | Effect of lnc13 Decrease |
|---|---|---|
| TRAF2 | Signal transduction in NF-κB pathway | Increased expression enhances inflammatory signaling |
| STAT1 | Mediates response to interferons | Increased expression amplifies immune activation |
| MYD88 | Adaptor protein in innate immunity | Increased expression strengthens inflammatory signals |
| IL1RA | Natural blocker of interleukin-1 | Altered balance contributes to inflammation |
The disease-associated version of lnc13 binds less effectively to hnRNPD, making it a weaker brake on inflammation 2 . This explains the genetic link between this genomic region and celiac disease risk.
While lnc13 represents a major breakthrough, it's just one piece of a larger puzzle. Recent research has identified other noncoding RNAs involved in celiac disease:
A 2025 genome-wide association study identified 15 novel genetic associations with celiac disease, including a significant locus in another long noncoding RNA gene called LINC01019 7 . This same region has been associated with rheumatoid arthritis, suggesting it may be a shared autoimmune locus .
Another study analyzing intestinal biopsies found that over 7,500 genes show altered expression in active celiac disease compared to controls 5 . Many of these are regulated by noncoding RNAs, creating a complex network of gene regulation.
| Research Tool | Application | Role in Discovery |
|---|---|---|
| RNA Sequencing | Comprehensive profiling of RNA molecules in tissues | Identified differential expression of thousands of genes in celiac biopsies 5 |
| Genome-Wide Association Studies (GWAS) | Scanning genomes to identify disease-associated variants | Located celiac-risk regions in noncoding areas including lnc13 locus 2 |
| RNA In Situ Hybridization | Visualizing RNA location within tissues | Confirmed lnc13 presence in intestinal lamina propria nuclei 2 |
| Knockdown/Overexpression Studies | Reducing or increasing specific RNA levels | Demonstrated causal relationship between lnc13 and inflammatory genes 2 |
The discovery of lnc13 and other noncoding RNAs in celiac disease opens exciting new avenues for patient care:
Drugs that restore lnc13 function or mimic its activity could potentially calm the inflammatory response in celiac disease, offering an alternative to strict gluten-free diets 1 .
Understanding a person's specific lnc13 variants might help predict disease severity or treatment response 1 .
At the 2025 Tampere Celiac Disease Symposium, researchers presented new findings on how lncRNAs like MAPKAPK5-AS1 modulate T cell activation and protect from intestinal damage in celiac disease 4 . This ongoing research highlights the growing recognition of noncoding RNAs as crucial players in celiac disease.
The discovery of lnc13 represents a fundamental shift in our understanding of celiac disease. We're moving beyond a simple story of genes and gluten to a much richer understanding of the epigenetic regulation that determines why some people develop the disease while others with the same HLA genes do not.
As research continues to unravel the complex interactions between noncoding RNAs, inflammatory pathways, and genetic susceptibility, we move closer to a future where celiac disease can be better diagnosed, managed, and perhaps even treated with targeted therapies that go beyond dietary restrictions alone.